Artificial devices are increasingly used in clinical medicine, both as diagnostic and therapeutic tools. Contact between such biomaterials and blood or tissue fluids may elicit adverse effects in the host if the material is not biocompatible. Contact between biomaterials and whole blood or tissue fluids takes place during extracorporeal treatments, such as cardiopulmonary bypass (CPB) and hemodialysis, and during implantation of devices into the cardiovascular system, such as heart valves, pumps and stents. It also occurs during implantations into soft and hard tissues, such as dental implants and various prostheses. In all these instances, surfaces that come in contact with blood are known to activate the cascade systems to varying degrees and thereby to induce adverse reactions in the patients undergoing these procedures. Complement activation triggered by biomaterials has been extensively investigated and is currently suggested to be of major importance for these adverse effects. However, the activation mechanisms and the role of this activation in the systemic inflammatory response are as yet poorly understood. Understanding these mechanisms is a prerequisite for finding tools to regulate the unwanted complement-related reactions of artificial surfaces. This is an application for an integrative research effort to design complement activation-inert biomaterials using various approaches. The proposed project will accomplish this goal by bringing together investigators with leading expertise in different fields (complement biology, structural biology, biomaterials) who share the same appreciation for the complexity of biological processes and are committed to addressing and elucidating the elements involved in the activation of complement by biomaterial and to designing complement activation-inert biomaterial. The specific contributions of each PI to this project are (i) whole blood models; (ii) unique knowledge of the interactions between cascade systems, cells and the biomaterial surface; and (iii) synthesis and functional characterization of complement inhibitors to be used in designing novel biomaterials. The Pis have a long history of scientific interaction that they will maintain and expand through the successful funding of this application. [unreadable] [unreadable]